Stress-related disorders such as major depressive disorder and post-traumatic-stress are serious mental illnesses that affect over 20 million Americans. Endocannabinoids, analogs of 9-THC, are neuromodulators implicated in regulating stress and anxiety. The long-term objective of this proposal is to determine the function of the endocannabinoid system in the etiology and pathophysiology of mood disorders. My recent work demonstrated that chronic mild stress, an animal model of depression, differentially regulates the cannabinoid receptor, CB1 receptor levels in a gender- specific manner in rats. Underlying this differential effect was the observation of basal sex differences in CB1 receptors with males expressing higher receptor densities than females. This leads to the general hypothesis that the endocannabinoid system is preferentially organized in male and female animals to respond differentially to chronic stress. Furthermore, given the higher sensitivity to stress in females than males, the upregulation of CB1 in females may serve to partially ameliorate the effects of stress. This hypothesis is based on the following observations: 1) Males have higher CB1 receptor densities than females under basal conditions 2) Chronic mild stress downregulates the CB1 in male rats 3) Chronic mild stress upregulates the CB1 in female rats, and 4) Disruption of CB1 receptor increases behavioral responses to stress and anxiety. However, it is unknown how stress-regulation of CB1 receptor affects synaptic neurotransmission and plasticity. Therefore, we hypothesize that the basal and stress-induced sex differences in hippocampal CB1 levels will be reflected as a sex difference in endocannabinoid neurophysiology. The two specific aims to be tested are: 1) To determine if CB1 receptor-mediated suppression of glutamate neurotransmission in the hippocampus differs as a function of gender under a) normal (non-stress) conditions and b) exposure to chronic mild stress, and 2) To determine if the induction of Long Term Potentiation (LTP) in the hippocampus differs as a function of gender under a) normal (non-stress) conditions and b) exposure to chronic mild stress. Specific hypotheses within each aim will be tested using in vitro extracellular electrophysiology, pharmacological and behavioral (chronic-mild-stress) techniques. PUBLIC HEALTH RELEVANCE: Mood disorders such as major depressive disorder and PTSD are serious mental illnesses that affect over 20 million Americans. Endocannabinoids, analogs of 9-THC, are neuromodulators implicated in regulating stress and anxiety. The function of the endocannabinoid system in the etiology and pathophysiology of mood disorders will be further assessed through an animal model of chronic stress and depression. Specifically, this project will assess the impact of stress on endocannabinoid-mediated neurotransmission.